Allogeneic Transplantation for MDS/AML Patients with Germline GATA2 Mutations

Background: Haploinsufficiency of GATA2 results in familial immunodeficiency and MDS/ AML. We present our experience with allogeneic stem cell transplant (HCT) for a family with germline GATA2 mutations.

Methods: After due IRB approval, the myeloid neoplasms data base at the Mayo Clinic, was queried for patients with germline GATA2 mutations.  A single family with 9 affected members was identified.  Clinical and laboratory data were retrospectively abstracted.

Results: All family members had a c1339A>C, pS447R germline GATA2 mutation (figure one). Unlike most other disease causing GATA2 mutations this mutation occurred in the non-zinc finger domain.  All 9 affected members have developed MDS/AML, with 3 having successfully undergone allo-HCT.

The proband presented with AML-MRC and +8. He had extensive HPV papillomas and a family history of MDS. He received standard induction chemotherapy and developed profound marrow aplasia and absidia sinusitis.  He underwent a reduced intensity conditioning 9/10 HLA-DQ MUD allo HCT. The transplant was complicated by CMV reactivation and acute grade 1 GI GVHD. His day 100 bone marrow biopsy has shown 100% donor chimerisms with no residual disease.

Patient No.2 was diagnosed to have MDS-RCMD. She underwent a myeloablative 10/10 HLA MUD transplant. She developed acute grade 1 Skin GVHD. Day 30 testing demonstrated a regenerating marrow, with no evidence for residual disease and 100 % donor chimerism.

Patient No.3 presented with refractory cytopenia with marrow dysgranulopoiesis and dysmegakaryopoiesis (Childhood MDS). She underwent a 9/10 HLA-DQ MUD transplant. Post-transplant course was complicated by C difficile infection and acute grade 1 skin GVHD. At day 30 she had 100 % donor chimerism.

Conclusion: Germline GATA2 mutations are associated with a high frequency of MDS/AML. We describe a family with a non-zinc finger GATA2 mutation causing MDS/AML, profound B/NK deficiency and viral warts and describe the successful role for allo-HCT in this setting.

       Table 1: Transplant Outcome

#

Δ

Prior Rx

HCT      -CI

CMV

Regimen

ABO/HLA

GVHD    Prop

aGVHD Status

Infection

Day 30 Chimerism /Marrow

Day 100 Chimerism /Marrow

Last Follow up (Days)

No1

AML

Idarubicin Cytarabine

0

D+ R+

Fludarabine  TBI (200)

ABO - Mismatch HLA 9/10

Tacrolimus MTX

GI Grade 1

E.Faecalis CMV

100% Donor/ 30 % Hypo- Cellular

100% Donor/ 30 % Hypo- Cellular

195

No2

MDS

None

0

D– R+

Busulfan Cytoxan

ABO -Match HLA 10/10

Tacrolimus MTX

Skin Grade 1

None

100% Donor/ 30 % Hypo- Cellular

NA

86

No3

MDS

None

0

D– R+

Cytoxan, TBI Alemtuzu-mab

ABO -Match HLA 9/10

Tacrolimus MTX

Skin Grade 1

C.difficile

100% Donor

NA

51